Publications by authors named "Katie Bergstrom"

20 Publications

  • Page 1 of 1

Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium.

Am J Hematol 2021 Nov 20;96(11):1491-1504. Epub 2021 Aug 20.

Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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http://dx.doi.org/10.1002/ajh.26310DOI Listing
November 2021

Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.

Mol Genet Genomic Med 2021 Apr 9:e1685. Epub 2021 Apr 9.

Department of Medicine, University of Cambridge, Cambridge, UK.

Background: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases.

Methods: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter cell line (HMEC1-BRE). Proteins were expressed for assessment of secretion and processing.

Results: Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum-derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9.

Conclusion: Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or "HHT-like" telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs.
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http://dx.doi.org/10.1002/mgg3.1685DOI Listing
April 2021

Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.

Hum Mutat 2020 11 30;41(11):1918-1930. Epub 2020 Aug 30.

Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.
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http://dx.doi.org/10.1002/humu.24092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857045PMC
November 2020

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3.

Int J Hematol 2019 Jul 23;110(1):95-101. Epub 2019 Mar 23.

Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Texas Children's Hospital, 1102 Bates St. Ste. C1025, Houston, TX, 77030, USA.

Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.
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http://dx.doi.org/10.1007/s12185-019-02626-wDOI Listing
July 2019

Correction: Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

Genet Med 2019 May;21(5):1261-1262

Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.

The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-019-0440-2DOI Listing
May 2019

Agents of empathy: How medical interpreters bridge sociocultural gaps in genomic sequencing disclosures with Spanish-speaking families.

Patient Educ Couns 2019 05 10;102(5):895-901. Epub 2018 Dec 10.

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, USA. Electronic address:

Objectives: To describe how linguistic tools used by interpreters during return of genomic sequencing results may have impacted communication with Spanish-speaking families, and to discuss the implications for the role of medical interpreters.

Methods: Using discourse analysis, we identified and categorized the various ways hospital-based interpreters adapted clinicians' language in 37 audio-recorded sessions in which Spanish-speaking parents participating in a clinical trial received their child's genomic sequencing results from English-speaking clinicians.

Results: We found that interpreters adapted clinicians' statements using five empathic linguistic tools: contextualization, encouragement, checking comprehension, endearment, and softening. Interpreters used an average of four linguistic tools per session, with contextualization and encouragement being the most frequently used.

Conclusions: Interpreters used empathic linguistic tools to alter clinicians' statements when communicating genomic information to Spanish-speaking families. Our findings demonstrate the critical role of interpreters as cultural mediators and facilitators of understanding for Spanish-speaking families.

Practice Implications: This study expands upon the definition of clinical empathy in interpreter-mediated sessions. Our findings suggest that revisions of standards of medical interpretation practice may be warranted regarding interpreters' ability to adapt clinicians' language in a culturally sensitive manner during interpretation.
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http://dx.doi.org/10.1016/j.pec.2018.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197396PMC
May 2019

Exome sequencing disclosures in pediatric cancer care: Patterns of communication among oncologists, genetic counselors, and parents.

Patient Educ Couns 2019 04 12;102(4):680-686. Epub 2018 Nov 12.

Department of Medicine, Baylor College of Medicine, 6620 Main St., Houston, TX 77030, United States; Department of Communication, Texas A&M University, TAMU 4234, College Station, TX 77843, United States; Center for Innovation in Healthcare Quality, Effectiveness, & Safety, Michael E. DeBakey Veterans Affairs Medical Center, 2450 Holcombe Blvd., Suite 01Y, Houston, TX 77021, United States. Electronic address:

Objective: To examine communication patterns and behaviors during disclosure of exome sequencing (ES) results to parents of pediatric cancer patients, and describe common themes in parental communication.

Methods: Using mixed methods, we analyzed transcripts of sessions where parents of pediatric cancer patients received ES results from an oncologist and genetic counselor. Seventy-six transcripts were analyzed for frequency of clinician information-giving, partnering-supportive talk, and active parent participation. A subset of 40 transcripts were analyzed using thematic content analysis.

Results: Disclosures consisted mostly of clinician talk (84% of total talk), which was focused on providing information (62% of clinicians' utterances) with occasional partnering-supportive talk (7% of clinicians' utterances). Most parents assumed a passive, listening role (16% of total talk). Themes in parental communication included expressing relief and the significance of an answer, concern about sharing results and responsibility for inheritance, and seeking clarification of health implications of results.

Conclusion: Our finding of low levels of active parent participation during ES disclosures highlights the need to improve patient/parent engagement and understanding in a genetic setting.

Practice Implications: Clinician communication strategies that could encourage parent participation and understanding include checking for parent understanding, partnership-building, and tailoring ES discussions to address parent concerns and preferences.
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http://dx.doi.org/10.1016/j.pec.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440863PMC
April 2019

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

Genet Med 2019 05 5;21(5):1100-1110. Epub 2018 Oct 5.

Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.

Purpose: Clinical sequencing emerging in health care may result in secondary findings (SFs).

Methods: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions.

Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care.

Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
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http://dx.doi.org/10.1038/s41436-018-0308-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450774PMC
May 2019

PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia.

Pediatr Blood Cancer 2019 01 10;66(1):e27439. Epub 2018 Sep 10.

Department of Pediatrics, Section of Hematology Oncology, Baylor College of Medicine, Houston, Texas.

Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.
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http://dx.doi.org/10.1002/pbc.27439DOI Listing
January 2019

Approaches to carrier testing and results disclosure in translational genomics research: The clinical sequencing exploratory research consortium experience.

Mol Genet Genomic Med 2018 11 21;6(6):898-909. Epub 2018 Aug 21.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington.

Background: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed.

Methods: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects.

Results: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results.

Conclusion: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.
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http://dx.doi.org/10.1002/mgg3.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305639PMC
November 2018

Undergraduate Student Perceptions and Awareness of Genetic Counseling.

J Genet Couns 2018 Aug 19. Epub 2018 Aug 19.

Genetic Counseling Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.

Genetic counseling is a rapidly expanding field, and the supply of certified genetic counselors is currently unable to keep up with job demand. Research is fairly limited regarding the awareness and perceptions that prospective genetic counseling students have on the field and what factors most influence their interest. The current study includes data collected from 1389 undergraduate students in the sciences at 23 universities across the United States who were surveyed regarding information related to their awareness, perceptions, knowledge, and interest in genetic counseling. The majority of participants had heard of genetic counseling (78.0%), many from a high school course (37.3%), college course (28.1%), or online (11.5%). Familiarity was associated with factors such as female gender (p = 0.003) and length of time in school (p < 0.001). After taking the survey, participant interest was positively associated with several factors including female gender (p < 0.001) and Asian and Hispanic ethnicity (p = 0.012). Factors commonly reported as attractive about the field included direct patient care, the variety of roles available, cultural competency and psychosocial training, and helping others. Discussion elaborates upon specific factors related to student awareness and interest in genetic counseling and potential ways to tailor recruitment strategies for maximum benefit to the field.
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http://dx.doi.org/10.1007/s10897-018-0284-yDOI Listing
August 2018

Portero versus portador: Spanish interpretation of genomic terminology during whole exome sequencing results disclosure.

Per Med 2017 11 21;14(6):503-514. Epub 2017 Nov 21.

Department of Communication, Texas A&M University, College Station, TX, USA.

Aim: Describe modifications to technical genomic terminology made by interpreters during disclosure of whole exome sequencing (WES) results.

Patients & Methods: Using discourse analysis, we identified and categorized interpretations of genomic terminology in 42 disclosure sessions where Spanish-speaking parents received their child's WES results either from a clinician using a medical interpreter, or directly from a bilingual physician.

Results: Overall, 76% of genomic terms were interpreted accordantly, 11% were misinterpreted and 13% were omitted. Misinterpretations made by interpreters and bilingual physicians included using literal and nonmedical terminology to interpret genomic concepts.

Conclusion: Modifications to genomic terminology made during interpretation highlight the need to standardize bilingual genomic lexicons. We recommend Spanish terms that can be used to refer to genomic concepts.
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http://dx.doi.org/10.2217/pme-2017-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393936PMC
November 2017

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

J Clin Invest 2017 Nov 3;127(11):4090-4103. Epub 2017 Oct 3.

Division of Pediatric Hematology, Hacettepe University Medical Faculty, Sihhiye, Ankara, Turkey.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.
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http://dx.doi.org/10.1172/JCI92876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663364PMC
November 2017

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features.

Am J Hum Genet 2017 Oct 21;101(4):503-515. Epub 2017 Sep 21.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.
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http://dx.doi.org/10.1016/j.ajhg.2017.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630163PMC
October 2017

Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle.

Cold Spring Harb Mol Case Stud 2016 Sep;2(5):a001057

Texas Children's Cancer Center and the Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;; Department of Molecular and Human Genetics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.

The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p.N546K) and PIK3CA (p.H1047R) and a germline pathogenic variant in PTPN11 (p.N308S) diagnostic for Noonan syndrome. The molecular landscape of RGNT is not well-described, but these data are consistent with prior observations regarding the importance of the interconnected MAPK and PI3K/AKT/mTOR signaling pathways in this rare tumor. The co-occurrence of FGFR1, PIK3CA, and PTPN11 alterations provides further evidence for consideration of RGNT as a distinct molecular entity from pediatric low-grade gliomas and suggests potential therapeutic strategies for this patient in the event of tumor recurrence as novel agents targeting these pathways enter pediatric clinical trials. Although RGNT has not been definitively linked with cancer predisposition syndromes, two prior cases have been reported in patients with RASopathies (Noonan syndrome and neurofibromatosis type 1 [NF1]), providing an additional link between these tumors and the mitogen-activated protein kinase (MAPK) signaling pathway. In summary, this case provides an example of the potential for genome-scale sequencing technologies to provide insight into the biology of rare tumors and yield both tumor and germline results of potential relevance to patient care.
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http://dx.doi.org/10.1101/mcs.a001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002928PMC
September 2016

Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis.

Pediatr Blood Cancer 2016 08 21;63(8):1484-7. Epub 2016 Apr 21.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

JAK2, MPL, and CALR mutations, which underlie essential thrombocythemia (ET) in most adults, are infrequent in children. Consequently, additional tests are needed to confirm pediatric ET diagnoses. We report a child with suspected ET and normal JAK2, MPL, and CALR analyses. Serum thrombopoietin (TPO) was markedly elevated, leading to analysis of the TPO gene, TPHO, which contains an upstream open reading frame (uORF) known to repress THPO translation. Sequencing revealed a de novo, germline stopgain mutation in the uORF, explaining the elevated TPO and thrombocytosis. This finding suggests that screening TPO levels and, if elevated, THPO 5' UTR sequencing could be diagnostic.
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http://dx.doi.org/10.1002/pbc.26032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916014PMC
August 2016

Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.

JAMA Oncol 2016 May;2(5):616-624

Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.

Importance: Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown.

Objective: To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors.

Design: Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record.

Main Outcomes And Measures: Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations.

Results: Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%).

Conclusions And Relevance: Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.
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http://dx.doi.org/10.1001/jamaoncol.2015.5699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471125PMC
May 2016

Pediatric Cancer Genetics Research and an Evolving Preventive Ethics Approach for Return of Results after Death of the Subject.

J Law Med Ethics 2015 ;43(3):529-37

Board-certified medical geneticist who focuses on laboratory and clinical research related to cancer susceptibility. She is a Professor in the departments of Pediatrics and Molecular and Human Genetics at Baylor College of Medicine. She is the Director of the Cancer Genetics and Genomics Program at Texas Children's Cancer and Hematology Centers. She received her M.D. and Ph.D. from Harvard University, Boston, MA.

The return of genetic research results after death in the pediatric setting comes with unique complexities. Researchers must determine which results and through which processes results are returned. This paper discusses the experience over 15 years in pediatric cancer genetics research of returning research results after the death of a child and proposes a preventive ethics approach to protocol development in order to improve the quality of return of results in pediatric genomic settings.
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http://dx.doi.org/10.1111/jlme.12295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617204PMC
January 2017

Obtaining informed consent for clinical tumor and germline exome sequencing of newly diagnosed childhood cancer patients.

Genome Med 2014 17;6(9):69. Epub 2014 Sep 17.

Texas Children's Cancer Center, 6701 Fannin Street #1400, Houston, TX 77030 USA ; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA ; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.

Background: Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures.

Methods: A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients.

Results: Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures.

Conclusions: An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken.
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http://dx.doi.org/10.1186/s13073-014-0069-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195891PMC
October 2014

Co-inheritance of mild hemophilia A and heterozygosity for type 2N von Willebrand disease: a diagnostic and therapeutic challenge.

Pediatr Blood Cancer 2014 Oct 7;61(10):1888-90. Epub 2014 Apr 7.

Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas.

Hemophilia A and von Willebrand disease are the two most common inherited bleeding disorders. Despite their frequency, however, there are very few reports of co-inheritance of the two disorders. We present the first report of a patient with mild hemophilia A and heterozygosity for type 2N von Willebrand disease (VWD). We discuss the patient's phenotype and highlight the diagnostic and therapeutic challenges caused by this co-inheritance.
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http://dx.doi.org/10.1002/pbc.25054DOI Listing
October 2014
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